Abstract In response to the growing societal burden of vascular and other AD related-dementias, NINDS has proposed ?Vascular Contributions to Cognitive Impairment and Dementia? (VCID) as a critical area of future research. VCID is the second leading cause of dementia and a major contributor to Alzheimer?s disease, the leading cause of dementia. VCID typically presents as progressive cognitive decline due to cerebral small vessel disease (CSVD). Risk factors for disease at the patient-level are well-understood and include age, hypertension, cigarette smoking, and diabetes. Furthermore, the end result of CSVD causing structural brain injury is well studied including white matter hyperintensities (WMH) on FLAIR, disrupted white matter microstructure on diffusion tensor imaging (DTI), lacunes, microbleeds, enlarged perivascular spaces, and atrophy. However, the link between patient-level vascular risk factors and endpoint pathologies is missing. There is a knowledge gap in the pathogenic mechanisms leading to CSVD progression and VCID. Indirect evidence suggests that ischemia is a key contributors to CSVD, but direct evidence in humans is lacking. Here, we propose a causal pathway linking vascular risk factors to, chronic ischemic-hypoxia, resulting in CSVD progression. We propose MR- oxygen extraction fraction (MR-OEF) as a tissue-specific biomarkers of hypoxia-ischemia due to CSVD. We postulate that MR-OEF can be used to understand CSVD pathogenesis such that targeted therapeutics can be developed, and to select patients who are at high or early risk of CSVD progression. Our preliminary data show that MR-OEF is elevated in the watershed region of older adults with WMH and correlates with WMH volume and with disruption of white matter microstructure in normal appearing white matter (NAWM). Therefore, we propose to determine: (1) the repeatability of watershed OEF measures, and the association between OEF and burden of white matter injury in CSVD; (2) if regionally elevated OEF predicts NAWM tissue ?at-risk? for WMH progression; (3) if baseline watershed OEF provides a patient biomarker to predict the progression of structural impairment and cognitive decline at follow-up; and (4) which specific modifiable risk factors correlate with change in watershed OEF across the study period. Given the aging society with increased duration of exposure to vascular risk factors, there is a critical need to identify predictors of: (1) CSVD progression defined using sensitive neuroimaging endpoints and (2) cognitive decline due to VCID. In this grant, we will serially image adults across a range of CSVD risk factors. We will test the ability of these biomarkers to predict progression of WMH and disrupted white matter microstructure. With successful completion of these aims, we will: 1) link specific hypoxia-ischemia to CSVD pathogenesis; 2) determine the optimal threshold of the MR-OEF biomarker that identifies individuals at risk for CSVD progression, enabling candidate selection in future clinical trials; and 3) identify modifiable risk factors which are closely tied to tissue hypoxia-ischemia, and which can be targeted for therapeutic intervention within clinical trials.